chr8-61503378-C-T

Variant names:

• chr8-61503378-C-T
• rs141861375
• NM_004318.4:c.2258G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004318.4(ASPH):​c.2258G>A​(p.Arg753His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,605,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R753C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: ASPH NM_004318.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.328
• Publications: 2 publications found

Genes affected

ASPH (HGNC:757): (aspartate beta-hydroxylase) This gene is thought to play an important role in calcium homeostasis. The gene is expressed from two promoters and undergoes extensive alternative splicing. The encoded set of proteins share varying amounts of overlap near their N-termini but have substantial variations in their C-terminal domains resulting in distinct functional properties. The longest isoforms (a and f) include a C-terminal Aspartyl/Asparaginyl beta-hydroxylase domain that hydroxylates aspartic acid or asparagine residues in the epidermal growth factor (EGF)-like domains of some proteins, including protein C, coagulation factors VII, IX, and X, and the complement factors C1R and C1S. Other isoforms differ primarily in the C-terminal sequence and lack the hydroxylase domain, and some have been localized to the endoplasmic and sarcoplasmic reticulum. Some of these isoforms are found in complexes with calsequestrin, triadin, and the ryanodine receptor, and have been shown to regulate calcium release from the sarcoplasmic reticulum. Some isoforms have been implicated in metastasis. [provided by RefSeq, Sep 2009]

ASPH Gene-Disease associations (from GenCC):

• facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03776169).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000197 (30/152172) while in subpopulation NFE AF = 0.000338 (23/68038). AF 95% confidence interval is 0.00023. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004318.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	NM_004318.4	MANE Select	c.2258G>A	p.Arg753His	missense	Exon 25 of 25	NP_004309.2
	ASPH	NM_001413844.1		c.2339G>A	p.Arg780His	missense	Exon 26 of 26	NP_001400773.1
	ASPH	NM_001413845.1		c.2303G>A	p.Arg768His	missense	Exon 26 of 26	NP_001400774.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPH	ENST00000379454.9	TSL:1 MANE Select	c.2258G>A	p.Arg753His	missense	Exon 25 of 25	ENSP00000368767.4	Q12797-1
	ASPH	ENST00000950798.1		c.2828G>A	p.Arg943His	missense	Exon 26 of 26	ENSP00000620857.1
	ASPH	ENST00000887974.1		c.2339G>A	p.Arg780His	missense	Exon 26 of 26	ENSP00000558033.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000320 AC: 78 AN: 243966 AF XY: 0.000303

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000658

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000574 AC: 834 AN: 1453552 Hom.: 0 Cov.: 29 AF XY: 0.000556 AC XY: 402 AN XY: 722688

African (AFR) AF: 0.00 AC: 0 AN: 33096

American (AMR) AF: 0.0000228 AC: 1 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25994

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39150

South Asian (SAS) AF: 0.0000471 AC: 4 AN: 84894

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5462

European-Non Finnish (NFE) AF: 0.000726 AC: 804 AN: 1107886

Other (OTH) AF: 0.000283 AC: 17 AN: 59978

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74338

African (AFR) AF: 0.000145 AC: 6 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000820 Hom.: 0

Bravo AF: 0.000325

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000387 AC: 47

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		0.33
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.052
Sift	Benign	0.27	T
Sift4G	Benign	0.14	T
Polyphen		0.0080	B
Vest4		0.028
MVP		0.13
MPC		0.042
ClinPred		0.060	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.083
gMVP		0.25
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs141861375; hg19: chr8-62415937;